Thiadicarbocyanine anthelmintic compositions and methods of using them



THIADICARBOCYANWE ANTHELMINTIC COM- BUSITIQNS AND ME'IHQDS OF USiNG Max C. McCowen and Paul F. Wiley, Indianapolis, Ind, assignors toEli Lilly and Company, Indianapolis, Ind., a corporation of-lndiana No Drawing. Application September 18, 1958. Serial No. 76.1,68i

11 Claims. (Cl. 16753) This is a continuation-in-part of our United. States patent application Serial Number 675,567, filed August 1, 1957 now abandoned.

This invention relates to therapeutic anthelmintic compositions and processes. More particularly, this invention is directed to therapeutic compositions containing certain thiadicarbocyanines, and acid addition salts thereof, and to methods of using them in the treatment of parasitic infections.

It iswell known that certain helminths are parasitic and infect especially the gastrointestinal tract of man and other animals. Such parasitic infection, or helminthiasis, is said to be the most prevalent disease in the World.

Helminthiasis has more manifest and serious consequences than the mere necessity of increasing nutrient intake by the host. In addition to. malnutrition, which almost inevitably is produced, the. diseased host may suffer from an extensive damage to intestinal mucosa resulting in hemorrhagingbecause of burrowing. and attachmentby' the parasite. Moreover, thetoxernia caused by absorption of excreta of the parasites, and the intestinal blocks produced in some advance and uncontrolled cases of helminthiasis can lead to prostration and death. It is obvious from the above, that helminthiasis is a disease of major concern and that it is, of utmost importance to have effective methods and therapeutic compositions as treatment.

It is an, object of this invention to provide for the treatment of helminthiasis, new and improved broad-spectrum pharmaceutical compositions free from heretofore encountered undesirable qualities. A further object of this invention is to provide a. safe, convenient and. effective processfor the treatment of helmintic infection. Other objects of the. invention will be apparent from the disclosure hereinafter made.

In accordance with the above and other objects, we have provided new broad-spectrum anthelmintic compositionsv comprising a suitable extending medium with which there is associated a dose amount of a thiadicarbocyanine salt represented by the following formula for example, a pharmaceutical extending medium. The

2,893,914 Patented July 7, 1959 extending medium can, and for human use preferably does; comprise atleast in part, a material of enteric character, that is, one which when associated with the medicament maintains the medicament in inert or inoperative form so long as the composition remains in the acidic stomach, butwhich releases the medicament when the composition reaches the intestine. By such means the medicament is rendered bland to the gastromucosa thereby avoiding the possibility of gastric irritation and upset.

The provision of such enteric property can be accomplished by coating the thiadicanbocyanine tablets. and the like with one of the commonly employed enteric coatings such as those containing fatty acids, shellacs, resins, cellulose derivatives, waxes, synthetic polymers, and thev like or combinations thereof, as, for example, those described in US. Patents No. 2,196,768, No. 2,373,- 763, No. 2,433,244, No. 2,455,790, No. 2,512,192, No. 2,540,979, and No. 2,714,084. We have found that a preferred coating composition, for the purpose of our invention comprises cellulose acetate phthalate. Alternatively, the medicament can be rendered enteric in character by adsorbingv it on a suitable adsorbent, such as a bentonite. The adsorbent-medicament combination can then be fabricated into tablets, filled capsules, suspensions, and the like. Thepreparations can contain additional ingredients; such, as butters, binders, preservatives, tfiavors, emulsifying agents, and the like, as may be. desired.

Although the. above. compositions are designed primarily for human use, they can also be employed in, suit: able dosage amountfor the treatment of animals, such as house pets and economically important domesticated and other animals, e.g., cattle, swine, and poultry. However, for the treatment of animals, it is generally more convenient to incorporate the thiadicarbocyanine in a physiologicall-y compatible excipient such as a dietary component of the animal. to be. treated. Thus, the animal can receive its medication with its. normal food intake. Alternatively, the thiadicarbocyanine compound can be associated in suitable dose amount witha physiologically compatible excipient which is edible, but is not a normal dietary constituent, and consequently may not be physiologically utilizable, for example, an ion exchange resin. Either type of blended mixture. can readily be administered to the animal by adding it to or mixing it with they feed of the animal in. proper dosage amount. If desired, the thiadicarbocyanine compound can be blended with a fabricated animal feed in such amount that the medicated feed when consumed, in normal daily quantity by the animal provides a therapeutically. effective dose amount of the thiadicarbocyaninecompound.

For. the, treatment of humans, the daily dosages of the thiadicarbocyanine compounds employed. in this invention desirably range from about 0.2 to about 2.0 grams, or from about 5 toabout 30 mg./kg. of body weight. The administration of such dose amounts daily is con? tinued for a period" of about two to twenty days. A preferred adult treatment consists of the oral administration of about 200 mg. of a thiadicarbocyanine compound in the form of enteric-coated tablets two or three times per day for about five to eight days. In the treatment of children, a preferred treatment is 5 mg./lb. of the childs weight given orally twice daily for five days, the, total, daily dose not exceeding about 600 mg If the infected child is very youngor if he does not readily ingest the, entericTcoated tablets, it is desirable to administer the medicament in the form of a suspension such as is disclosed hereinafter. It is to be understood, however, that the daily dosages and the length of treatment are largely dependent upon cond tions such as age and general physical condition of the. infected'patient, severity and nature of the infection, action of the therapy.

For veterinary purposes in the treatment of animals,

the thiadicarbocyanine compound preferably is administered daily in single or divided quantities in the amount of about 5 to about 30 mg./kg. of animal body weight, and administration is continued for a period of about three to twenty or more days. The presently preferred treatment regimen comprises a treatment period of about ten to twenty days and a daily dose amount of about 15 to 20 rug/kg. of body weight. An alternative mode of treatment is the maintenance of the animal on a lesser dosage amount of thiadicarbocyanine compound than the preferred range mentioned above, for a relatively long period of time. By such means the animal is gradually freed from helminth infection and is maintained free from infection. This mode of treatment is adaptable to andthe desired rapidity of about 20 mg. of 3,3'-diethylthiadicarbocyanine per milli-- liter of suspension, and especially adapted for pediatric use, is prepared as follows:

5 g. of 3,3'diethylthiadicarbocyanine iodide are added with stirring to an admixture of 0.4 g. of potassium hydroxide and about 125 ml. of water. About ten minutes subsequent to the above addition, ml. of a liquid soap are introduced to the mixture with continued stirring, followed by the addition of 50 ml. of a basic aqueous solution (1.2 g. of potassium hydroxide) to which has been added 3.2 g. of phenolphthalein. ml. of 2 N hydrochloric acid are added dropwise to the mixture with gentle stirring until a gelatinous formation results. The

animals being groomed for slaughter and marketing,

important helminths as roundworms, threadworms, hook- 1 worms, pinworms, and poultry worms, thereby providing the enhanced safety and convenience of the long-sought but previously unavailable broad-spectrum anthelmintic therapy. A further virtue of this broad-spectrum treatment is that it provides for the first time eflective oral anthelmintic therapy against whipworm infection whereas the heretofore known narrow-spectrum treatments of whipworm infection were relatively ineffective in addition to requiring hospitalization and enema administration.

The employment of the compositions described herein affords advantages not heretofore realizable. We have; for the first time, provided broad-spectrum anthelmintic compositions which are substantially free from unwanted side reactions such as vomiting, nausea, dizziness, diarrhea, epigastric pain and the like reactions which were inevitable attendants of previously known anthelmintics. Moreover, the compositions and methods of this invention appear to cause no damage to tissues such as those of the kidneys and liver, such as has been observed fol lowing the administration of other anthelmintic compositions. Moreover, with previously available methods of treating helminthiasis, auxiliary procedures were often necessary such as pretreatment fasting, enema administration, and purgation. However,in the employment of our novel compositions, such supportive or supplemental measures are neither required nor advisable.

The thiadicarbocyanines employed in our compositions can be synthesized by the method described by Sitnik and Steingardt in Journal of Applied Chemistry (U.S.S.R.) 9, 1842 (1936). By this method salts are supplied 'in which the anion associated with the thiadicarbocyanine is iodide, ethyl sulfate, and the like. Other salts such as for example the chloride, bromide, phenolphthalein, and the like can be made from the above-mentioned iodide or of 3,3'-diethylthiadicarbocyanine iodide.

stirring is then accelerated and is continued until a bright blue precipitate forms. The precipitate which comprises the phenolphthalein salt of 3,3'-diethylthiadicarbocyanine is separated by filtration, is washed twice with 3300 ml. volumes of water, and is air dried. About 18.75 g. of methyl celllose (viscosity 1500 centipoises) is dissolved in a mixture of 30 m1. of glycerin and 30 ml. of water. To the methyl cellulose solution is added with sufliciently gentle stirring to prevent foaming an aqueous solu-. tion consisting of 950 ml. of water, 0.15 g. of butyl-phydroxybenzoate, 0.30 g. propyl-p-hydroxybenzoate and 0.30 g. methyl-p-hydroxybenzoate. To the resulting mixture are added with continued gentle stirring 2.25 g. of anhydrous magnesium sulfate, 1.50 g. of sodium chloride and.4.5 g. of soluble saccharin.

' 8.75 g. of a purified bentonite (sold under the trademark Veegum by The R. T. Vanderbilt Co.) and 60.0 g. of the phenolphthalein salt of 3,3diethylthiadicarbocyanine are uniformly mixed, and 300 ml. of water are added to the solid mixture with stirring to form a smooth paste. The paste is added with stirring to the methyl cellulose solution, and then are added 1.5 ml. of wild cherry extract and 0.27 ml. of an anti-foam agent acceptable for use in food products. The volume of the mixture is brought to 1500 ml. by the addition of distilled water, the mixture is homogenized, and is bottled.

Tablets 1100 g. of starch are mixed thoroughly with 1000 3. To the mixture are added about 3400 g. of starch in the form of an aqueous starch paste, and the resulting mixture is granulated in the usual manner. To the granulation are added a 7 mixture of 130 g. of starch powder and about 26 g. of

other anionic salts by methods well known to the art. I

The iodide is a preferred salt because of the relat ve ease of its preparation. I

The following are illustrative of preparations incorporating. a thiadicarbocyanine salt to provide novel compositions of this invention.

Filled gelatin capsules Enterlc type suspension An aqueous suspension of the phenolphthalein salt of 3,3 diethylthiadicarbocyanine, constituted to contain magnesium stearate, and the whole is mixed to form a uniform composition. The mixture is then compressed on a tableting machine into tablets of such size as to provide about 100 mg. of thiadicarbocyanine salt per tablet.

The tablets can be provided with a simple sugar coating and bottled. Preferably, however, they are coated with an enteric coating, for example, cellulose acetate phthalate. The enteric coating is applied in the custom- -ary manner by coating-the tablets in a rotating coating pan with alternate layers of cellulose acetate phthalate and talc until a coating of sufiicient thickness is obtained. The coated tablets are then preferably given a final sugar coating.

Veterinary preparation The following ingredients are combined and thoroughly mixed to provide 100 kg. of a premix suitable for use in the treatment of house pets such as cats and dogs.

Dried skim milk 20 Corn oil meal 25 Dried meat scraps 5 Soybean oil meal 5 Vanilla cookie crumbs 2S Toasted comflakes 14 .3,,3-diethylthiadicarbocyanine iodide 6 The foregoing palatable mixture can be sprinkled upon ormixed with such food as the animal is to receive,

amount of mixture used being sufficient to provide a therapeutic quantity of the thiadicarbocyanine. compound; Alternatively, the mixture can be employed as a premix,

in which case it can be distributed to feed manufac-- turers, such as manufacturers of commercial dog and eat foods, for incorporation in prepared foods, for ex-- Veterinary preparation.

The following ingredients are combined and thoroughly mixed to provide 100 kg. of'a mixture especially suitable for use in the treatment of animals, especially the herbivorous type, and poultry:

K-g. Soybean oil meal- 80 3,3-diethylthiadicarbocyanine iodide 20 The mixture can be employed in the same manner as the foregoing veterinary preparation, as by adding it in suitable dose amount to one or more components of the animals feed at the time of feeding, or by using the mixture as a premix and incorporating it in suitable dose amount with a complete or substantially complete feed. Thus for example, a medicated feed suitable for administration to feeder steers is obtained by blending pounds of the mixture with 2000 pounds of a feed of a type commonly known as supplement and grain ration, which may be a total ration or one to be further supplemented by hay or roughage.

Administration to a feeder steer weighing about 1000 pounds of about 30 pounds of the medicated feed per day provides a dose amount of thiadicarbocyanine compound of about mg./kg. of steer body weight.

We claim:

1. A broad-spectrum anthelmintic medicated feed composition in dosage unit form, comprising a thiadicarbocyanine represented by the following formula Ciiiii/ wherein R is a lower alkyl radical and X is a physiologically compatible anion, dispersed in a utilizable feedstuff.

2. A broad-spectrum anthelmintic medicated feed composition in dosage unit form comprising a thiadicarbocyanine represented by the following formula ciiiilo Q HHHHH C mama dispersed in a utilizable feedstufi.

6%- 4. A broadaspectrum. anthelmintic. composition. come.- prising a thiadicarbocyanine represented. by the. follow. ing formula Ciii.t t O wherein R is a lower alkyl radical and X is a physiologically compatible anion, said tablet being surrounded by an enteric coating.

6. A broad-spectrum anthelmintic dosage unit in enteric-coated tablet form, said tablet comprising a solid pharmaceutical extending medium and a thiadicarbocyanine represented by the following formula and said tablet being surrounded by an enteric coating. 7. A broad-spectrum anthelmintic dosage unit in tablet form, said tablet comprising a solid pharmaceutical extending medium and at least about 0.1 gram of a thiadicarbocyanine represented by the following formula Cii ilG I) N a and said tablet being surrounded by a cellulose acetate phthalate enteric coating.

8. A method of treating helminthiasis which comprises orally administering to a host infected with helminthiasis repeated doses of a thiadicarbocyanine represented by the following formula oiiiilo Q I wherein R is a lower alkyl radical and X is a physiolog ically compatible anion.

9. A method of treating helminthiasis which comprises orally administering to a host infected with helminthiasis repeated daily dose amounts of about 5 to about 30 milligrams per-kilogram of host body weight of a thiadicarbocyanine represented by the following formula o iiiii=o U wherein R is a lower alkyl radical and X is a physiologically compatible anion.

u 10. A method of treating helminthiasis which comprises orally administering to a host infected with helminthiasis -repeated daily dose amounts of about 5 to about 30 milligrams per kilogram of host body weight of a thiadicarbocyanine represented by the following formula r 11. A method of treatin'ghelminthiasis which comprises orally administering to a host infected with helminthiasis repeated dailydose amounts of about 5 to about 30 milligrams per kilogram of host body weight of a thiadicarbocyanine represented by the following formula (I \oiiiil/ K] (Ema-P- (52m wherein P represents the phenolphthalein anion. 

1. A BROAD-SPECTRUM ANTHELMINTIC MEDICATED FEED COMPOSITION IN DOSAGE UNIT FORM, COMPRISING A THIADICARBOCYANINE REPRESENTED BY THE FOLLOWING FORMULA 